Our overall program is interested in fundamental issues regarding the evolution and chemotherapeutic potential of polyketide natural products. Using the power of organic synthesis, we seek to learn about the specific structural features found in polyketides, their effect on conformation, and the importance of conformation on biological activity. An underlying theme of this work is the development of practical methods applicable to the synthesis of stereochemically complex structural fragments found in polyketide natural products. During the research period, cationic cyclopropane methodology previously developed in our lab will provide access to ambruticin J, the putative biosynthetic intermediate to the antifungal agent ambruticin S. This material will be used to explore both chemical as well as biochemical conversion of ambruticin J to ambruticin S. The biochemical studies, performed in collaboration with Rolf Muller (University of Saarland) will provide fundamental information regarding the role of several post-PKS proteins including the epoxidase, AmbJ. In addition, intermediates necessary for ambruticin J synthesis will be converted to several labelled SNAC esters for feeding studies with the producing organism as well as isolated proteins. Analysis of the feeding studies will provide important information with regard to the unique biosynthesis of these cyclopropane containing polyketides. Section II of the Research Plan proposes new methodology, ether-transfer, applicable to the synthesis of acyclic polyketide fragments, pyran structural units and spiroketals. Like the cyclopropane methodology, ether-transfer is an efficient process that proceeds through a unique carbocationic intermediate and rapidly modifies simple starting materials into stereochemically complex synthetic fragments. Applications of the methodology include an efficient synthesis of the polyketides, diospongin A and B as well as neopeltolide. Biological and conformational studies on the neopeltolide polyketide core are proposed as a precursor to analogue design.

Public Health Relevance

Our overall program is interested in fundamental issues regarding the evolution and chemotherapeutic potential of polyketide natural products. An underlying theme of this application is the development of practical methods applicable to the synthesis of complex structural fragments found in polyketide natural products. Synthetic and biosynthetic studies will investigate natural products shown to possess antifungal and anticancer activity.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM084922-04
Application #
8456204
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2010-05-01
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
4
Fiscal Year
2013
Total Cost
$279,440
Indirect Cost
$93,147
Name
University of Notre Dame
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
824910376
City
Notre Dame
State
IN
Country
United States
Zip Code
46556
Stefan, Eric; Nalin, Ansel P; Taylor, Richard E (2013) Concise enantioselective synthesis of diospongins A and B. Tetrahedron 69:7706-7712
Liu, Kai; Arico, Joseph W; Taylor, Richard E (2010) Application of stereoselective ether transfer to the synthesis of isotactic polyethers. J Org Chem 75:3953-7